{"title":"E26 transformation-specific transcription factor 3 tips the balance: repressing tropomyosin 2 to fuel Yes-associated protein 1-driven cisplatin resistance in ovarian cancer.","authors":"Yan Wang, Zhujing Xu, Chanfeng He, Huiling Qu, Yiting Yang, Yongzheng Lu, Xiaojuan Dong","doi":"10.1097/CAD.0000000000001761","DOIUrl":null,"url":null,"abstract":"<p><p>Cisplatin resistance remains a major challenge in the treatment of ovarian cancer, significantly limiting therapeutic efficacy. This study aimed to investigate the role of E26 transformation-specific transcription factor 3 (ELK3) in cisplatin resistance and elucidate the underlying molecular mechanism involving the tropomyosin 2 (TPM2)-Yes-associated protein 1 (YAP1) signaling axis. By silencing ELK3 and TPM2 in combination with cisplatin treatment, the regulatory effects of ELK3 and TPM2 on cisplatin sensitivity in ovarian cancer cells were evaluated. The interaction between ELK3 and the TPM2 promoter was verified via chromatin immunoprecipitation and dual-luciferase reporter assays. Western blotting was used to assess the expression of DNA damage marker gamma-histone H2AX and YAP1 to investigate the role of TPM2 in ELK3-mediated signaling and drug response. Cisplatin treatment markedly increased ELK3 expression. Knockdown of ELK3 enhanced cisplatin sensitivity by suppressing cell proliferation, promoting apoptosis, and increasing DNA damage. Mechanistically, ELK3 was directly bound to the promoter region of TPM2 and repressed its transcription. Downregulation of TPM2 subsequently led to increased activation of the YAP1 signaling pathway. Rescue experiments demonstrated that silencing TPM2 reversed the chemosensitizing effects of ELK3 knockdown. These findings highlight the ELK3/TPM2/YAP1 axis as a critical regulator of cisplatin resistance. By suppressing TPM2 and subsequently activating YAP1 signaling, our study identified ELK3 as a crucial transcriptional repressor that contributes to cisplatin resistance in ovarian cancer.</p>","PeriodicalId":7969,"journal":{"name":"Anti-Cancer Drugs","volume":" ","pages":""},"PeriodicalIF":2.2000,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Anti-Cancer Drugs","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1097/CAD.0000000000001761","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"ONCOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Cisplatin resistance remains a major challenge in the treatment of ovarian cancer, significantly limiting therapeutic efficacy. This study aimed to investigate the role of E26 transformation-specific transcription factor 3 (ELK3) in cisplatin resistance and elucidate the underlying molecular mechanism involving the tropomyosin 2 (TPM2)-Yes-associated protein 1 (YAP1) signaling axis. By silencing ELK3 and TPM2 in combination with cisplatin treatment, the regulatory effects of ELK3 and TPM2 on cisplatin sensitivity in ovarian cancer cells were evaluated. The interaction between ELK3 and the TPM2 promoter was verified via chromatin immunoprecipitation and dual-luciferase reporter assays. Western blotting was used to assess the expression of DNA damage marker gamma-histone H2AX and YAP1 to investigate the role of TPM2 in ELK3-mediated signaling and drug response. Cisplatin treatment markedly increased ELK3 expression. Knockdown of ELK3 enhanced cisplatin sensitivity by suppressing cell proliferation, promoting apoptosis, and increasing DNA damage. Mechanistically, ELK3 was directly bound to the promoter region of TPM2 and repressed its transcription. Downregulation of TPM2 subsequently led to increased activation of the YAP1 signaling pathway. Rescue experiments demonstrated that silencing TPM2 reversed the chemosensitizing effects of ELK3 knockdown. These findings highlight the ELK3/TPM2/YAP1 axis as a critical regulator of cisplatin resistance. By suppressing TPM2 and subsequently activating YAP1 signaling, our study identified ELK3 as a crucial transcriptional repressor that contributes to cisplatin resistance in ovarian cancer.
期刊介绍:
Anti-Cancer Drugs reports both clinical and experimental results related to anti-cancer drugs, and welcomes contributions on anti-cancer drug design, drug delivery, pharmacology, hormonal and biological modalities and chemotherapy evaluation. An internationally refereed journal devoted to the fast publication of innovative investigations on therapeutic agents against cancer, Anti-Cancer Drugs aims to stimulate and report research on both toxic and non-toxic anti-cancer agents. Consequently, the scope on the journal will cover both conventional cytotoxic chemotherapy and hormonal or biological response modalities such as interleukins and immunotherapy. Submitted articles undergo a preliminary review by the editor. Some articles may be returned to authors without further consideration. Those being considered for publication will undergo further assessment and peer-review by the editors and those invited to do so from a reviewer pool.